Currently, 22 million people 12 and older need treatment for illicit drug/alcohol abuse in the US (2013 SAMHSA survey), costing the government $468 billion dollars/year in related expenses such as health care. The purpose of the proposed research is to investigate inhibitory GABA cells as a novel target of drugs of abuse in the ventral tegmental area (VTA), the reward center of the brain, with the long-term goal of applying information we attain to addiction treatment strategies. This research fits directly with the NIH mission to investigate the neurobiological and behavioral mechanisms underlying drug abuse and addiction. Within the VTA, dopamine-containing cells are involved in motivation and reward. Reward is an essential component of survival, mediated by increased dopamine release from the VTA. Drugs of abuse dramatically enhance dopamine levels beyond normal rewarding behaviors, and cause synaptic modifications on VTA cells, leading to the diseased state of addiction. Addiction is the compulsive drive to self-administer drugs even after mitigation of dopamine enhancements and in spite of the resulting negative consequences. While known that illicit drugs cause synaptic modifications to synapses directly on dopamine cells, how these drugs alter GABA neuron synaptic connections is almost completely unknown. This is despite the fact that GABA neuron activity is involved in vivo in both the perception and associative learning of reward. Therefore, examining VTA GABA cells is extremely important as they play a role in reward while little information exists regarding how these cells normally modulate their synapses (e.g. synaptic plasticity), or how drugs of abuse alter that plasticity. We hypothesize that excitatory synapses on VTA GABA cells will exhibit synaptic plasticity. It is anticipated that drugs of abuse will alter this normal synaptic plasticity, which could potentially be a contributor to addiction. Using single cell electrophysiology, we will record VTA GABA cells and demonstrate that these cells exhibit synaptic modifications in response to afferent input, and in combination with pharmacology examine the receptor/signaling pathway involved. We will then use electrophysiology and drugs of abuse applied either acutely and via IP injection for either 1 or 7-10 day chronic treatments. We anticipate that drugs of abuse will occlude or alter this plasticity, demonstrating this pathway's potential involvement in addiction. In the future, optogenetics use will enable the activation of specific circuits and inputs. In this way, the behavioral in vivo impact on reward of the excitatory pathway can be examined. The combination of techniques to investigate these aims including a model that allows for the positive identification of GABA cells genetically is a powerful approach to test our hypothesis. As currently there are no good treatments to address addiction, the identification of a novel target for drugs of abuse could lead to new avenues of treatment by providing a novel target to examine.